EBV is a causative agent in endemic Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals, causing a variety of proliferative disorders including immunoblastic lymphomas, oral hairy leukoplakia, and an unusual tumor of muscle origin in immunosuppressed children. EBV is also a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin lymphoma, Burkitt's lymphoma, and gastric carcinoma. The pathologies suggest a wide variety of tissue tropism for EBV in vivo. In vitro and in vivo, the cells that are most susceptible to EBV infection and permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) that is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gB, gH, gL, and gp42. gp42 has been specifically found to bind to human leukocyte antigen (HLA) class II and this interaction is required for EBV entry into B lymphocytes. To date, little is known about the mechanism that EBV uses to bind and penetrate B cells. This proposal will analyze the role of gp42 and its interaction with HLA for viral entry by structure-function studies. Clarifying the interactions between cellular receptors and viral glycoproteins is essential for understanding the tropisms behind EBV associated diseases. PUBLIC HEALTH RELEVANCE: This proposed research represents a collaborative research program between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases and the proposed research may result in the identification of new therapeutics for EBV infections as well as the herpesvirus family in general of which EBV is a member.